The exocrine portion of the pancreas regulates digestion and is an important modulator of nutrient uptake. Abnormalities in exocrine pancreas function can lead to serious conditions such as pancreatitis and pancreatic cancer. The hormonal control of the exocrine pancreas has been well-studied in regards to cholecystokinin (CCK)-induced stimulation of the digestive enzyme secretions. Our recent studies show that fibroblast growth factor 15 (FGF15) is a secreted endocrine hormone that promotes gallbladder filling and opposes CCK-induced contraction of the gallbladder (9). Based on our preliminary data, our hypothesis is that FGF15 acts as a broader anti-CCK signal and counter-regulates exocrine pancreas secretions. FGF15 signaling through FGF receptors also functions together with nuclear receptors to regulate transcriptional responses in the liver (19). Since the pancreas expresses these same nuclear receptors, we predict that the same pathways will be also be operative. The long term goals of this project are to explore the role of FGF15 in regulating exocrine pancreas function by both rapid and transcriptional mechanisms. In the first aim, I will address whether FGF15 regulates exocrine pancreas digestive enzyme secretion by rapid mechanisms. This will be accomplished by testing the ability of FGF15 to oppose the pancreas secretions induced by various stimulants in vivo. In addition, this aim will determine the ability of FGF15 to directly oppose enzyme secretions from isolated pancreas cells in vitro. I will also use proteomic analysis of pancreatic secretions to evaluate differences in WT and previously-generated mice that lack FGF15. In the second aim, I will examine the intracellular signaling and transcriptional responses involved in FGF15 regulation of exocrine pancreas function. This will involve exploring the role of the intracellular messenger, cyclic AMP, as well as Mitogen-Activated Protein Kinase (MAPK) pathways in mediating FGF15 responses using both in vivo and in vitro approaches. Finally, I will investigate whether FGF15 regulates gene expression in the exocrine pancreas using QPCR methods. Several mouse lines with deficient expression of individual components of nuclear receptor or FGF signaling will be used for this analysis. FGF receptor signaling is implicated in the pancreatitis and exocrine pancreatic cancer pathologies (23), yet treatments for these conditions are still lacking. Therefore, understanding the hormonal regulation of exocrine pancreas function by FGF15 may yield new therapeutic avenues with high potential for pharmacological intervention by targeting membrane receptors. [unreadable] [unreadable] [unreadable]